The silver lining of induced pluripotent stem cell variation

Abstract

Induced pluripotent stem cells (iPSCs) are being generated using various reprogramming methods and from different cell sources. Hence, a lot of effort has been devoted to evaluating the differences among iPSC lines, in particular with respect to their differentiation capacity. While line-to-line variability should mainly reflect the genetic diversity within the human population, here we review some studies that have brought attention to additional variation caused by genomic and epigenomic alterations. We discuss strategies to evaluate aberrant changes and to minimize technical and culture-induced noise, in order to generate safe cells for clinical applications. We focus on the findings from a recent study, which compared the differentiation capacity of several iPSC lines committed to the hematopoietic lineage and correlated the differential maturation capacity with aberrant DNA methylations. Although iPSC variation represents a challenge for the field, we embrace the authors' perspective that iPSC variations should be used to our advantage for predicting and selecting the best performing iPSC lines, depending on the desired application.

Addressing variability in iPSC-derived models of human disease: guidelines to promote reproducibility

“…Lastly, several groups reported that variation in routine cell culturing and maintenance such as variation in passage number, growth rate and culture medium contribute to iPSC variability (Fossati et al, 2016;Hu et al, 2010;Schwartzentruber et al, 2018;Volpato et al, 2018), and that automated platforms can reduce such variability (Paull et al, 2015). Our own group has also recently shown that laboratory-based sources of variation, even when different laboratories follow standardised protocols, can substantially overpower genotypic effects.…”

Peripheral blood-derived monocytes show neuronal properties and integration in immune-deficient rd1 mouse model upon phenotypic differentiation and induction with retinal growth factors

“…1 a (i, ii)). These cells were differentiated into reconditioned monocytes (RM) by culturing them in media consisting IL-3, MCSF and β-ME in a low serum environment as reported earlier [ 17 ]. The monocytes upon de-differentiation became larger in size, rounded and formed colonies by day 6 in culture (Fig.…”

Transcriptome dynamics along axolotl regenerative development are consistent with an extensive reduction in gene expression heterogeneity in dedifferentiated cells

“…A troublesome aspect of processes that concur with cell dedifferentiation is the accentuated heterogeneity detected at genetic, epigenetic, and phenotypic levels ( Almendro, Marusyk & Polyak, 2013 ; Burrell et al, 2013 ; Fossati, Jain & Sevilla, 2016 ; Krishna et al, 2016 ; Ling et al, 2015 ; Meacham & Morrison, 2013 ). Such heterogeneities are of great concern because they can limit the response to treatment of cancerous cell, or the reproducibility of healthy clonal tissues and individuals derived from animal and plant induced dedifferentiated cells ( Almendro, Marusyk & Polyak, 2013 ; Burrell et al, 2013 ; Fossati, Jain & Sevilla, 2016 ; Krishna et al, 2016 ; Ling et al, 2015 ; Meacham & Morrison, 2013 ). Intriguingly, a chromatin relaxation-based extensive reduction in gene expression heterogeneity for dedifferentiated cells could promote long-term phenotypic heterogeneities following cell dedifferentiation by increasing genetic and epigenetic mutagenic potential and the phenotypic relevance of preexisting or newly generated mutations for dedifferentiated cells.…”